ABSTRACT Millions of children receive anesthesia each year for surgical and diagnostic procedures, with children also experiencing prenatal exposures when their mothers undergo surgery during pregnancy. The safety of anesthetics during brain development has been questioned because preclinical models have shown that anesthesia exposure during brain maturation disrupts neurodevelopment, and clinical and epidemiological studies have found that early childhood exposure to anesthesia may be associated with neurocognitive deficits later in life. There is however still uncertainty about the clinical studies because the data are conflicting, and the available literature is limited due to residual confounding, selection bias, small sample size, and inadequate length of follow-up. Prenatal exposures are particularly relevant because this period is characterized by high fetal sensitivity to neurotoxic agents and correlates to the developmental stage associated with peak brain vulnerability in preclinical studies of anesthetic neurotoxicity. While the Food and Drug Administration (FDA) has recently released a warning against the use of anesthetic drugs in pregnant women in the third trimester, this warning was based on animal studies, with no studies evaluating the effect of fetal anesthetic exposure on brain development in humans. Studying prenatal exposure is challenging because large numbers of linked maternal- child records with long durations of follow up in the children are required. In this study, we will evaluate a national cohort of 2.7 million linked mothers and children who are Medicaid beneficiaries, and identify mothers exposed to anesthesia for surgical procedures during pregnancy. The Aims of the proposed study are to: (1) Assess the association between exposure to anesthesia for common surgical procedures during pregnancy in mothers and neurodevelopmental disorders in their children, (2) Evaluate the impact of exposure during different periods of gestation, and (3) Determine the increased risk of neurodevelopmental disorders associated with longer durations of prenatal exposure. A tapered multivariate matching method will be used to match exposed and unexposed mothers on demographic and medical characteristics, with potential confounders and mediators also assessed. Cox proportionate hazards modeling, respecting the matched sets, will be used to evaluate the association between prenatal exposure to anesthesia and neurodevelopmental disorder. Prior observational studies of anesthesia exposure and neurodevelopmental outcome have been confounded by the presence of the underlying medical comorbidity in patients who need surgery. Prenatal exposures however offer a unique opportunity because the exposure to anesthesia stems from the need to address a medical condition in the mother, and not from any medical comorbidity in the child. As a result, this will allow for the evaluation of children who received anesthesia without an underlying medical condition requiring surgery. Data generated from this work will therefore inform the providers and families about the risk of prenatal exposure, but also provide a better overall understanding of anesthetic neurotoxicity in the developing brain. !